Arthritis is a progressive, inflammatory autoimmune disease. The most prevalent form of arthritis is rheumatoid arthritis, a chronic inflammatory disorder which is characterised by inflammation of the joints. Although rheumatoid arthritis rarely leads to mortality, the associated symptoms of rheumatoid arthritis, which most typically include the loss of joint mobility, can cause a significant impairment to an individual's quality of life.
Rheumatoid arthritis (RA) is typically multiarticular, that is that it affects many joints. Once triggered, it results in inflammation of the synovium, leading to edema, vasodilation and activation of CD4+ T cells. Early and intermediate markers of disease progression include the expression of the cytokines; tumour necrosis factor alpha, IL-1, IL-6, IL-8 and IL-15 as well as transforming growth factor (TGF). Once inflammation of the joint occurs, the synovium thickens, while the cartridge disintegrates. This series of events results in joint destruction and loss of joint mobility.
Therapeutic approaches used to treat RA generally target the mediators of inflammation. In particular, tumour necrosis factor inhibitors have been widely prescribed to subject presenting with this condition. Other therapies relate to anti-CD20 antibodies, interleukin-1 (IL-1) blockers, as well as blockers of T cell activation.
Toll-like receptors (TLRs) form a family of pattern recognition receptors which have a key role in activating the innate immune response. 11 Toll-like receptors have been identified in humans to date. The members of the TLR family are highly conserved, with most mammalian species having between 10 to 15 TLRs. Each TLR recognises specific pathogen-associated molecular signatures. Toll-like receptor 2 (TLR2, CD282, TLR-2) is activated by peptidoglycan, lipoproteins and lipoteichoic acid. Toll-like receptors are known to form either homodimers or heterodimers wherein each dimer has a different ligand specificity. TLR2 forms a heterodimer with either TLR1 or TLR6 and perhaps also with TLR10 as a membrane bound receptor. In addition, the ectodomain of TLR2 forms a soluble heterodimers with CD14 in the circulatory system and milk.
Ligand binding to TLR2 results in downstream signalling mediated by interaction with cytoplasmic adaptor proteins such as MyD88 and Mal (MyD88-adaptor like) also known as TIRAP (Toll-Interleukin-1 receptor domain containing adaptor protein). The implication of TLR2 and TLR2-induced signalling and immune system activation has implicated TLR2 as an important mediator in the development of inflammation and disease. Accordingly there has been significant therapeutic interest in relation to the modulation of the TLR2 signalling pathway. It is recognised that the identification that TLR2 mediated immune signaling has importance in inflammation and disease has resulted in a number of therapeutic approaches being designed which serve to block or suppress the function activity of TLR2.
The inventors have surprisingly identified that TLR2-mediated IL-8 (interleukin 8) cytokine production is involved, as an important pro-inflammatory mediator, in the development and progression of rheumatoid arthritis.
Without wishing to be bound by theory, the inventors predict that compounds present in the synovial fluid of subjects presenting with rheumatoid arthritis cause activation of Toll-like Receptor 2 (TLR2), this in turn results in intracellular signalling which is mediated by Toll-like Receptor 2, which causes the expression of mediators, such as pro-inflammatory cytokines, which cause a pro-inflammatory response. In particular, and with reference to the onset and progression of rheumatoid arthritis, the inventors have shown that Toll-like Receptor 2 activation results in intracellular signalling which results in the production of the pro-inflammatory cytokine IL-8, and the associated development of a pro-inflammatory immune response.
The inventors have therefore identified that blocking the activation or suppressing the function or intracellular capability of Toll-like Receptor 2 will, in turn, result in a reduction in the production of IL-8, this in turn causing a down-regulation of the aberrant immune response which characterises the development of rheumatoid arthritis in a subject.